Reentrant mechanisms play a primary role in many types of cardiac arrhythmias. Functional reentry, in the form of spiral waves, underlies many tachycardias as well as fibrillation, but the dynamic properties of spiral wave stability and breakup are still not well characterized. Previous work from our lab has demonstrated that sustained spiral wave activity can be induced and systematically studied in monolayers of cultured neonatal rat ventricular cells. The focus of this work will be on the properties of spiral waves, and particularly how they are influenced by islands of tissue heterogeneities that include altered ion channel expression, gap junctional coupling, and ectopic foci. Tissue engineering approaches will be utilized to permit a systematic evaluation of different types of heterogeneities at specified locations. We propose to use voltage- and calcium-sensitive dyes and multi-site optical mapping to track the reentrant activity in cardiac cell monolayers. We will test the hypotheses, (1) Regional differences in cellular membrane properties can anchor reentrant waves and alter cycle length, (2) Heterogeneities in tissue microstructure result in discontinuous propagation and amplify the anchoring effects of anatomical obstacles, (3) Lines of block during reentry originate from microheterogeneities, and their length is modulated by excitability, wavelength and tissue anisotropy, (4) Islands of altered ion channel expression may suffice to initiate spiral wave breakup, particularly under conditions of reduced cell-cell coupling, and (5) Triggered activity and afterdepolarizations can cause spiral wave breakup but require critical mass and critical coupling.
These aims exploit the properties of the cultured cell monolayer as a well-controlled, versatile and quantitative experimental model for basic studies of clinically important, reentry-based arrhythmias. ? ?
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